Identification of functionally distinct leukocyte subpopulations combined with the recognition of the roles played by their surface proteins have created new opportunities for hematopoietic reconstitution and immune modulation, and provide the underlying rationale for this program project application. The proposed program brings together the collective expertise of investigators who have identified cell surface molecules that mediate immunomodulatory and alloimmune effects, developed techniques for isolating and activating rare types of mononuclear leukocytes, and demonstrated their therapeutic effects in model systems. The objective of our program is to utilize these discoveries to develop more effective immune cell based therapies, both autologous and allogeneic, for disorders ranging from malignancies to autoimmune disorders and graft-versus-host disease (GVHD). Four projects are described. Two of these projects seek to exploit the immunotherapeutic potential of dendritic cells pulsed with tumor derived antigens; one focuses on a treatment for malignant lymphoma a tumor of hematopoietic origin. while the other focuses on colorectal carcinoma a solid tumor. Two additional projects address novel approaches to the treatment and prevention of GVHD. One addresses the dual role of a polymorphic cell surface molecule, CD3 1, which appears to play an important pathogenetic role in GVHD; the other focuses on the ontogeny and mechanism of action of immunoregulatory CD3+,CD4-, CD8- T cell's derived from bone marrow. Supporting these projects are two cores, including an administrative and biostatistical core that will provide budgetary oversight, assistance in protocol design and statistical analysis and a flow cytometry core that will provide surface phenotype analysis and cell sorting capabilities. We believe that this interdisciplinary and highly interactive program will ultimately lead to the development of new and more potent forms of cell based immunotherapies for a variety of life-threatening disorders.